The lysine acetyltransferase PCAF is a key regulator of arteriogenesis-猫眼课题宝

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2013

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A. Bastiaansen;M. Ewing;H. D. Boer;Tineke C. van der;Pouw Kraan;M. D. Vries;Erna A. B. Peters;Sabine M. J. Welten;Ramon;Arens;S. Moore;J. Faber;J. Jukema;J. Hamming;-A.;Y. Nossent;P. Quax

目的-治疗性动脉生成，即，使用单作用因子疗法对预先存在的侧支进行扩张性重塑并不像预期的那样成功。调节作为相关基因程序的主开关的因子可能被证明更有效。转录共激活因子P300/CBP相关因子（PCAF）具有组蛋白乙酰化活性，促进多种炎症基因的转录。由于动脉生成是一个炎症驱动的过程，我们假设PCAF作为动脉生成的多因子调节剂。方法和结果-在诱导后肢缺血后，PCAF −/−小鼠和用药理学PCAF抑制剂Garcinol治疗的健康野生型小鼠的血流恢复受损，证明PCAF在动脉生成中的重要作用。PCAF缺乏降低了参与动脉生成的白细胞和血管细胞的体外炎症反应。体内基因表达谱分析显示，PCAF缺乏导致动脉形成过程中3505个基因的差异表达，更具体地说，导致多个促炎基因的诱导受损。此外，在PCAF−/−小鼠中，骨髓中炎症细胞，特别是“促炎性”Ly 6C hi单核细胞的募集严重受损。结论：这些发现表明PCAF在有效动脉生成所需的炎症过程中起着主开关的作用。在该报告中，对HLI后24小时从股薄肌显微解剖的侧枝进行了全基因组微阵列分析。在这里，我们发现了非常多的差异表达的基因，然后在WT小鼠的股薄肌侧枝中发现上调的404个基因39。使用整个内收肌群进行微阵列分析，不仅侧支，而且浸润的白细胞和周围的非血管组织也包括在这些分析中。

Objective— Therapeutic arteriogenesis, i.e., expansive remodeling of pre-existing collaterals, using single-action factor therapies has not been as successful as anticipated. Modulation of factors that act as a master switch for relevant gene programs may prove more effective. Transcriptional co-activator P300/CBP-associated factor (PCAF) has histone acetylating activity and promotes transcription of multiple inflammatory genes. Because arteriogenesis is an inflammation-driven process, we hypothesized that PCAF acts as multifactorial regulator of arteriogenesis. Approach and Results— After induction of hind limb ischemia, blood flow recovery was impaired in both PCAF −/− mice and healthy wild type mice treated with the pharmacological PCAF inhibitor Garcinol, demonstrating an important role for PCAF in arteriogenesis. PCAF deficiency reduced the in vitro inflammatory response in leukocytes and vascular cells involved in arteriogenesis. In vivo gene expression profiling revealed that PCAF deficiency results in differential expression of 3505 genes during arteriogenesis and, more specifically, in impaired induction of multiple pro-inflammatory genes. Additionally, recruitment from the bone marrow of inflammatory cells, in particular “pro-inflammatory” Ly6C hi monocytes, was severely impaired in PCAF−/− mice. Conclusions— These findings indicate that PCAF acts as master switch in the inflammatory processes required for effective arteriogenesis. In that report, a whole-genome microarray analysis was performed on collaterals microdissected from the gracilis muscle 24 hours after HLI. Here we found exceedingly more differentially expressed genes, then the 404 genes that were found upregulated in gracilis collaterals of WT mice 39 . Using the entire adductor muscle group for microarray analysis, not only the collaterals but also infiltrating leukocytes and surrounding nonvascular tissues were included in these analyses.

The lysine acetyltransferase PCAF is a key regulator of arteriogenesis

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